Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.25.1 (proteasome)
 28,817 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cystic fibrosis (CF) is a lethal monogenetic disease characterised by impaired water and ion transport over epithelia. The lung pathology is fatal and causes death in 95% of CF patients. The genetic basis of the disease is a mutation in the cystic fibrosis transmembrane conductance regulator (CFTR), a cAMP-regulated chloride channel. The most common mutation, DeltaF508, results in a protein that cannot properly be folded in the endoplasmic reticulum, is destroyed and hence does not reach the apical cell membrane. This paper will discuss those pharmacological approaches that are directed at correcting the defect in ion transport. At present, no clinically effective drug is available, although research has defined areas in which progress might be made. These are the following: (1) the drug 4-phenylbutyrate (4PBA) increases the expression of DeltaF508-CFTR in the cell membrane, probably by breaking the association between DeltaF508-CFTR and a chaperone; (2) a number of xanthines, in particular 8-cyclopentyl-1, 3-dipropylxanthine (CPX), are effective in activating CFTR, presumably by direct binding and also possibly by correcting the trafficking defect; (3) the isoflavone genistein can activate both wild-type and mutant CFTR, probably through direct binding to the channel; (4) purinergic agonists (ATP and UTP) can stimulate chloride secretion via a Ca(2+)-dependent chloride channel and in this way compensate for the defect in CFTR, but stable analogues will be required before this type of treatment has clinical significance; (5) treatment with inhaled amiloride may correct the excessive absorption of Na(+) ions and water by airway epithelial cells that appears connected to the defect in CFTR; although clinical tests have not been very successful so far, amiloride analogues with a longer half-life may give better results. The role of CFTR in bicarbonate secretion has not yet been established with certainty, but correction of the defect in bicarbonate secretion may be important in clinical treatment of the disease. Currently, major efforts are directed at developing a pharmacological treatment of the ion transport defect in CF, but much basic research remains to be done, in particular, with regard to the mechanism by which defective CFTR is removed in the endoplasmic reticulum by the ubiquitin-proteasome pathway, which is a central pathway in protein production and of significance for several other diseases apart from CF.
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PMID:Pharmacological treatment of the ion transport defect in cystic fibrosis. 1111 77

Adenylyl cyclase toxin of Bordetella pertussis has been shown by several investigators to require Ca(2+) for its actions on target cells, but little is known about the nature and specificity of divalent metal binding to this novel toxin. Calcium is the preferred divalent metal since toxic actions are markedly reduced in the presence of divalent species other than calcium. Mn(2+) EPR was used to quantitate and characterize divalent metal binding and revealed that the toxin contains approximately 40 divalent metal sites, consisting of at least one class of high-affinity sites that bind Mn(2+) with a K(D) of 0.05 to 0.35 microM and one or more classes of lower affinity sites. Water proton relaxation data indicate that approximately 30 of these sites are completely inaccessible to bulk solvent. Our observations, together with the sequence homology between adenylyl cyclase toxin and the alkaline protease of Pseudomonas aeruginosa, indicate that the formation of five beta-sheet helices within the repeat domain of the toxin upon binding Ca(2+) is required for cell intoxication.
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PMID:Structural consequences of divalent metal binding by the adenylyl cyclase toxin of Bordetella pertussis. 1169 53

The extensive pentachlorophenol (PCP) contamination and its increasing treatment costs motivate the search for a more competitive treatment alternative. In a municipal wastewater treatment plant, anaerobic sludge-handling processes comprises three bio-processes, namely the anaerobic sludge digestion, post-sludge digestion and sludge land application, which reduce sludge organic content and make sludge a good fertilizer for land application. Availability and effectiveness make the anaerobic sludge handling processes potential technologies to treat PCP-contaminated soil. The technical feasibility of using anaerobic sludge bioprocesses was studied by treating PCP soil in two pilot digesters to simulate the primary sludge digestion, in serum bottles to mimic the post-sludge digestion, and in glass pans to represent the on-site sludge application. For primary digestion, the results showed that up to 0.98 and 0.6 mM of chemical and soil PCP, respectively, were treated at nearly 100% and 97.5% efficiencies. The PCP was transformed 95% to 3-MCP, 4.5% to 3,4-DCP, and 0.5% to 3,5-DCP. For post-digestion, 100% pure chemical PCP and greater than 95% soil PCP were removed in less than 6 months with no chlorophenol residues of any kind. Complete removal of PCP by-products makes this process a good soil cleanup method. For on-site treatment, PCP was efficiently treated by multiple sludge application; however, the PCP residue was observed due to the high initial PCP content in soil. Overall, more mass PCP per unit sludge per day was processed using the primary sludge digestion than the on-site soil treatment or post-sludge digestion. And, sludge acclimation resulted in better PCP treatment efficiencies with all three processes.
Water Sci Technol 2001
PMID:Treating an aged pentachlorophenol- (PCP-) contaminated soil through three sludge handling processes, anaerobic sludge digestion, post-sludge digestion and sludge land application. 1179 46

According to the rule of academican E. N. Pavlovskiy, any organism of host is an environment of inhabit for a parasite (Pavlovskiy, 1934). It was analysed, which "ecological niche" or microbiotop (= microhabitat) is occupied by this or that species of symbiotic (parasitic) copepods in organisms of different groups invertebrate-hosts. The assumption lying in a basis of the given analysis means that each group of hosts may give to cohabitants only certain variants of microbiotopes independently on the general morphological structure and life mode of hosts. Five types of microbiotops offered by various groups of hosts for symbiotic copepods are designated (Ta[symbol: see text] 2). 1. The body surface of benthic invertebrates as a microbiotope is characterized by conditions being little different (concerning any kind of physical and chemical influences on copepods) from those in external environment on any other substrate. Apparently a trophical dependence plays a determining role in this case. There are certain directions in a development of adaptations, which are characteristic in some extent for all water ectoparasitic crustaceans and have one functional task--to help to an ectoparasite to keep itself on a surface of host body. In the first, the maxillules and maxillipeds significantly are developed, they get a form of large claws, with which the dopepods are strongly attached on a surface of host body and have an opportunity to move on it without a danger to be washed off. In the second, the form of the body undergoes a dorso-ventral expression and expansion of prosome, forms a cephalic shield allowing to the symbiont to press itself tightly to the host body surface and to avoid the loss of host (tab. 2). In occasions, some ectoparasites stimulate the formation of galls in skin tissues of the host, that also provides the parasite with constant conditions, without any threat to lose the host. However, this phenomenon has not a wide distribution and is observed in some groups of crustacean and echinoderm hosts. 2. The narrow tubular cavities in the organism of host either they are a part of external environment (as in channel system of spongia) or a part of internal environment of organism (as channels of blood system or thin parts of a digestive system) have always rigidly limited sizes and form. Characteristics of all parasites occupying this microbiotopes are the strong transformations. They are expressed by the reduction of legs or any other appendages (frequently in a significant degree), loss of segmentation to some extent and in eruciform (or vermiform) form of a body (tab. 2). This microbiotope is occupied by an ectoparasite in one case only (Spongicola uncifer from channel system of spongia) and by endoparasites in all other cases. 3. Large cavities connected with external environment. The formations of various genesis, such as mantle cavity of molluscs, gill cavity and marsupium of crustaceans, bursal cavity of ophiuroids and branchial cavity of ascidians, concern this type of microbiotopes. All of them are characterized by the relative difference from the external environment and rather large volume (in comparison to sizes of copepods), that provides the parasites with a sufficient protection from factors of the external environment and constant source of food such as elements of host body or food's particles brought by the water flow. Morphological changes in inhabitants of the microbiotope have two directions. They practically are absent in the overwhelming majority copepods, living in the mantle of cavity of the lamellibranches. On the other hand, the inhabitants of gill cavity and marsupium of crustaceans, bursal cavities of ophiuroids and branchial cavity of ascidians are characterized by the presence of strong transformations. Usually there are expressed in a loss of segmentation to some extent, reduction of appendages and swelling of body, as in species of the genus Sphaeronella (tab. 2). Changes are also observed in the life cycle: the tendency to reduce stages of development (development of nauplii stage, which takes place under the ovarial cover). In this case the copepodid stages hatch from the ova. 4. The internal cavity of organism of host. This type of microbiotopes in different groups of the hosts is represented in a various degree. We recognise it in a coelome of polychaetes, lacunar system of molluscs, mixocoel of crustaceans, coelome of echinoderms and cavity of body in ascidians. Two basic evolutionary directions are observed in copepods occupying this microbiotope. In the first case, the parasite is not exposed to transformations and keeps the initial plan of structure as in ancestral free-living forms. In the second case the parasites are exposed to strong transformations, they either live directly in cavity's liquid, or are surrounded by a cyst (as in Cucumaricolidae). 5. Microbiotope of the last type is most specific. The simultaneous existence in two environments--external environment (environment of the second order) and internal environment (environment of the first order) leads to the complete loss of ancestral type in a structure and level of organisation. At the same time both morphological and functional division of the parasite body into two parts produces a new formation--the ectosome and endosome. In this case we deals with the phenomenon of mesoparasitism.
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PMID:[Some peculiarities of the relationships between parasitic copepods and their invertebrate hosts]. 1187 Dec 55

Degradation of the HIV receptor CD4 by the proteasome, mediated by the HIV-1 protein Vpu, is crucial for the release of fully infectious virions. To promote CD4 degradation Vpu has to be phosphorylated on a motif DSGXXS, which is conserved in several signalling proteins known to be degraded by the proteasome upon phosphorylation. Such phosphorylation is required for the interaction of Vpu with the ubiquitin ligase SCF-beta-TrCP that triggers CD4 degradation by the proteasome. In the present work, we used two peptides of 22 amino acids between residues 41 and 62 of Vpu. Vpu41-62 was predicted to form an alpha-helix-flexible-alpha-helix including the phosphorylation motif DS52GNES56 and Vpu_P41-62 was phosphorylated at the two sites Ser52 and Ser56. We analysed the conformational change induced by the phosphorylation of this peptide on the residues Ser52 and Ser56. Homo- and heteronuclear NMR techniques were used to assess the structural influence of phosphorylation. The spectra of the free peptides, Vpu_P41-62 and Vpu41-62, in both H2O (at pH 3.5 and 7.2) and a 1:1 mixture of H2O and trifluoroethanol were completely assigned by a combined application of several two-dimensional proton NMR methods. Analysis of the short- and medium-range NOE connectivities and of the secondary chemical shifts indicated that the peptide segment (42-49) shows a less well-defined helix propensity. The Vpu_P41-62 domain of residues 50-62 forms a loop with the phosphate group pointing away, a short beta-strand and a flexible extended 'tail' of residues 60-62. Residues 50-60 exhibit alpha-proton NMR secondary chemical shift changes from random coil toward more beta-like structure with the combined (temperature, solvent and pH) NMR and molecular calculation experiments. Differences in this molecular region 50-62 suggest that conformational changes of Vpu_P play an important role in Vpu_P-induced degradation of CD4 molecules.
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PMID:HIV-1 encoded virus protein U (Vpu) solution structure of the 41-62 hydrophilic region containing the phosphorylated sites Ser52 and Ser56. 1189 91

Bioremediation of consecutive spills of phenol, 2-chlorophenol (2-MCP), 2,4,6-trichlorophenol (2,4,6-TCP) and pentachlororphenol as single pollutants was investigated in eight pilot plant scale sand columns system (100 cm l, 6 cm ID), simulating the conditions, which could be created in the saturated zone of a pristine aquifer following an accidental spill. Bioremediation in this study consisted of re-circulating local groundwater through the polluted site in a controlled manner following a closed-loop configuration. Intrinsic microbial development was enhanced by adding the necessary nutrients. Consecutive accidental spills of 480-mg phenol/kg soil; 140-mg 2-MCP/kg; 14-mg 2,4,6-TCP/kg soil and 17-mg pentachlorophenol (PCP)/kg soil under saturated conditions and a continuous specific discharge of 0.56 cm min(-1) were simulated. Degradation curves demonstrated first-order kinetics. Biodegradation rates (k1) were influenced by consecutive exposures. Calculated rate constants for biodegradation for sole substrate experiments were in the range of 0.06-0.15 day(-1), 0.21-1.20 day(-1), 0.04-2.28 day(-1) and 0.01-0.03 day(-1) for phenol, 2-MCP, 2,4,6-TCP and PCP, respectively. The acclimation of the aquifer to simulated consecutive accidental spills was found to be directly proportional to the cumulative load of each single chlorophenol. A relationship between the octanol water partitioning (Kow) values and the experimental degradation rates (k1) was found.
Water Res 2003 Jan
PMID:Simulation of bioremediation of chlorophenols in a sandy aquifer. 1246 6

Next to water, tea is the most popular beverage in the world, and the cancer-preventive effects of this beverage have been suggested. Epidemiological studies have shown decreased cancer occurrence in those individuals who drink green tea regularly. A wealth of research suggests numerous mechanisms of action to explain these observations. The most abundant and popular compound studied in tea research is (-)-epigallocatechin-3-gallate (EGCG), which acts as a powerful antioxidant and can inhibit a number of tumor cell proliferation- and survival-related proteins. Tea polyphenols are known to inhibit the large multi-catalytic protease (the proteasome) and metaloproteionases, involved in tumor survival and metastasis, respectively. Additionally, tea polyphenols inhibit the activities of many tumor-associated protein kinases, including epidermal growth factor receptor, vascular endothelial growth factor receptor, platelet-derived growth factor receptor, mitogen-activated protein kinase, and IkB kinase. Tea polyphenols have also been found to inhibit some cancer-related proteins that regulate DNA replication and transformation. At present, it is not known which of these activities of tea polyphenols are required for its cancer-preventive effects. However, by understanding the in vivo concentrations of tea polyphenols required to inhibit each of these activities, we may start to sort out in the future the mechanisms responsible for the cancer-preventive effects of tea.
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PMID:Potential molecular targets of tea polyphenols in human tumor cells: significance in cancer prevention. 1249 82

Lithium fluoride thermoluminescence (TL) detectors, with different Li composition (Li-6 and Li-7) and various activators (LiF:Mg,Ti, LiF:Mg,Cu,P), are widely used for dosimetry in space. The primary radiation field in space is composed of fast electrons, protons and heavy charged particles (HCP). By its interaction with the structures of the spacecraft, this field may be modified inside the crew cabin. Therefore, calibration of TL detectors against a dose of gamma-rays is not sufficient for relating the TL readout to absorbed dose or to quantities relevant in radiation protection, without suitable correction. We introduce and calculate the detection efficiency, eta, relative to gamma-ray dose, of lithium fluoride detectors after proton and heavy charged particle (HCP) irradiation. We calculate eta for MCP-N (LiF:Mg,Cu,P) and for MTS-N (LiF:Mg,Ti) using microdosimetric models. The microdosimetric distributions used in these models (for HCP of charges between Z=1 to Z=8 and in the energy range between 0.3 MeV/amu and 20 MeV/amu) are calculated using an analytical model, based on the results of Monte Carlo simulated charged particle tracks using the MOCA-14 code. The ratio etaMCP-N/etaMTS-N for protons of stopping power (in water) below 10 keV/microm lies in the range between 0.65 and 1.0 and for HCP with Z>1--between 0.3 and 0.6. The stopping power of the particle is found not to be a unique parameter to scale the response of TL detectors. The combination of response of LiF:Mg,Cu,P and LiF:Mg,Cu,P detectors can be more suitable for a dose correction in space radiation fields.
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PMID:Modeling the response of thermoluminescence detectors exposed to low- and high-LET radiation fields. 1279 31

A distinct 8 kDa calcium-binding protein (CaBP) is preferentially expressed at the cercarial stage during the life-cycle of the schistosome. Available data indicate that this CaBP may be associated with tissue/organ remodelling (involving protein degradation and synthesis of new proteins) during transformation of the cercariae from free-living form in water to parasitic life in the vertebrate host. Many CaBP molecules (e.g. calmodulin) show Ca(++)-dependent interaction with target proteins and thus modulate their activity. Accordingly, the parasite 8 kDa CaBP was used as a probe to clone and identify putative target protein(s) directly by binding interaction. Screening of schistosome lambdagt11 expression library with radio-iodinated CaBP yielded several overlapping clones showing Ca(++)-dependent binding of the CaBP. Sequence analyses revealed that these clones encode the S5a/Rpn10 multiubiquitin-binding protein which is a component of the regulatory 19S subunit of the 26S proteasome. The schistosome molecule, designated SmS5a, is 420 amino acids long. The nearly full length molecule (Gln3-Ser420) as well as the amino terminal (N-S5a, Gln3-Gly200) and carboxyl-terminal (C-S5a, Asp225-Ser420) portions were synthesized in bacteria, purified, and antibodies to the parasite SmS5a were prepared. Interaction between SmS5a and the 8 kDa CaBP in a Ca(++)-dependent manner was found under various experimental conditions: CaBP-Sepharose bound soluble SmS5a, immobilized SmS5a bound soluble CaBP, and complex formation was found when both molecules were in solution. Furthermore, it was shown that the C-terminal portion of SmS5a, but not the N-terminal portion of the molecule, reacted with the CaBP. SmS5a synthesized in a cell-free system and Western blots revealed 2 species, conceivably corresponding to the naked molecule (approximately 50 kDa) and the molecule subjected to post-translational modification (approximately 70 kDa). The present studies suggest that proteasome activity may be modulated by calcium, and this modulation is mediated via CaBP molecule(s).
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PMID:Interaction of the proteasome S5a/Rpn10 multiubiquitin-binding protein and the 8 kDa calcium-binding protein of Schistosoma mansoni. 1463 20

A series of vinyl drug esters was synthesized using acyclovir and chloramphenicol with different carbon chain length acyl donors by alkaline protease from Bacillus subtilis and Lipozyme respectively, in non-aqueous medium. The corresponding vinyl drug derivatives were confirmed by nuclear magnetic resonance and infrared spectrometry. The influences of different organic solvents, reaction time, temperature, and content of water on synthesis of vinyl chloramphenicol esters were studied.
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PMID:Enzyme catalyzed synthesis of some vinyl drug esters in organic medium. 1504 99


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